Nutrition and cognition across the lifetime: an overview on epigenetic mechanisms

  • Received: 22 April 2021 Accepted: 12 July 2021 Published: 15 July 2021
  • The functioning of our brain depends on both genes and their interactions with environmental factors. The close link between genetics and environmental factors produces structural and functional cerebral changes early on in life. Understanding the weight of environmental factors in modulating neuroplasticity phenomena and cognitive functioning is relevant for potential interventions. Among these, nutrition plays a key role. In fact, the link between gut and brain (the gut-brain axis) is very close and begins in utero, since the Central Nervous System (CNS) and the Enteric Nervous System (ENS) originate from the same germ layer during the embryogenesis. Here, we investigate the epigenetic mechanisms induced by some nutrients on the cognitive functioning, which affect the cellular and molecular processes governing our cognitive functions. Furthermore, epigenetic phenomena can be positively affected by specific healthy nutrients from diet, with the possibility of preventing or modulating cognitive impairments. Specifically, we described the effects of several nutrients on diet-dependent epigenetic processes, in particular DNA methylation and histones post-translational modifications, and their potential role as therapeutic target, to describe how some forms of cognitive decline could be prevented or modulated from the early stages of life.

    Citation: Arianna Polverino, Pierpaolo Sorrentino, Matteo Pesoli, Laura Mandolesi. Nutrition and cognition across the lifetime: an overview on epigenetic mechanisms[J]. AIMS Neuroscience, 2021, 8(4): 448-476. doi: 10.3934/Neuroscience.2021024

    Related Papers:

  • The functioning of our brain depends on both genes and their interactions with environmental factors. The close link between genetics and environmental factors produces structural and functional cerebral changes early on in life. Understanding the weight of environmental factors in modulating neuroplasticity phenomena and cognitive functioning is relevant for potential interventions. Among these, nutrition plays a key role. In fact, the link between gut and brain (the gut-brain axis) is very close and begins in utero, since the Central Nervous System (CNS) and the Enteric Nervous System (ENS) originate from the same germ layer during the embryogenesis. Here, we investigate the epigenetic mechanisms induced by some nutrients on the cognitive functioning, which affect the cellular and molecular processes governing our cognitive functions. Furthermore, epigenetic phenomena can be positively affected by specific healthy nutrients from diet, with the possibility of preventing or modulating cognitive impairments. Specifically, we described the effects of several nutrients on diet-dependent epigenetic processes, in particular DNA methylation and histones post-translational modifications, and their potential role as therapeutic target, to describe how some forms of cognitive decline could be prevented or modulated from the early stages of life.



    Alzheimer's disease


    Amyotrophic Lateral Sclerosis


    Brain-Derived Neurotrophic Factor


    body mass index


    CREB-binding protein


    Central Nervous System


    docosahexanoic acid


    DNA methyl-transferase


    Developmental Origin of Health and Disease


    epigallocatechin gallate


    Enteric Nervous System


    eicosapentaenoic acid


    fetal alcoholic syndrome


    fetal alcohol spectrum disorders


    Frontotemporal Dementia


    histone acetyl-transferases




    histone deacetylases


    histone methyl-transferases


    Insulin-like growth factor-2


    long chain polyunsaturated fatty acids


    late onset Alzheimer's disease


    mild cognitive impairment


    methyl-CpG-binding protein


    Parkinson's disease


    Paternal Origin of Health and Disease


    retinoic acid receptor-α






    short-chain fatty acids


    vitamin A deficiency


    vitamin D receptor.



    This study was supported by funding from the Project “Bando Ricerca Competitiva 2017”, University of Naples Parthenope (D.R.289/2017) to L.M. and from the Department of Humanities, University of Naples Federico II (Fondi ricerca dipartimentale 2020 and 2021) to L.M.

    Conflict of interest

    All authors declare no conflicts of interest.

    [1] Gelfo F, Mandolesi L, Serra L, et al. (2018) The neuroprotective effects of experience on cognitive functions: evidence from animal studies on the neurobiological bases of brain reserve. Neuroscience 370: 218-35. doi: 10.1016/j.neuroscience.2017.07.065
    [2] Beauquis J, Roig P, De Nicola AF, et al. (2010) Short-term environmental enrichment enhances adult neurogenesis, vascular network and dendritic complexity in the hippocampus of type 1 diabetic mice. PLoS One 5: e13993. doi: 10.1371/journal.pone.0013993
    [3] Ambrogini P, Lattanzi D, Ciuffoli S, et al. (2013) Physical exercise and environment exploration affect synaptogenesis in adult-generated neurons in the rat dentate gyrus: possible role of BDNF. Brain Res 1534: 1-12. doi: 10.1016/j.brainres.2013.08.023
    [4] Bacon ER, Brinton RD (2021) Epigenetics of the Developing and Aging Brain: Mechanisms that Regulate Onset and Outcomes of Brain Reorganization. Neurosci Biobehav Rev 125: 503-516. doi: 10.1016/j.neubiorev.2021.02.040
    [5] Mandolesi L, Gelfo F, Serra L, et al. (2017) Environmental factors promoting neural plasticity: Insights from animal and human studies. Neural Plast 2017: 7219461. doi: 10.1155/2017/7219461
    [6] Troisi Lopez E, Cusano P, Sorrentino P (2020) The relationship between sports activity and emotions in the formation of cognitive processes. J Phys Educ Sport 20: 2349-2353.
    [7] Mandolesi L, Polverino A, Montuori S, et al. (2018) Effects of physical exercise on cognitive functioning and wellbeing: Biological and psychological benefits. Front Psychol 9: 509. doi: 10.3389/fpsyg.2018.00509
    [8] Jirout J, LoCasale-Crouch J, Turnbull K, et al. (2019) How lifestyle factors affect cognitive and executive function and the ability to learn in children. Nutrients 11: 1953. doi: 10.3390/nu11081953
    [9] Murphy T, Dias GP, Thuret S (2014) Effects of diet on brain plasticity in animal and human studies: mind the gap. Neural Plast 2014: 563160. doi: 10.1155/2014/563160
    [10] Cutuli D (2017) Functional and structural benefits induced by omega-3 polyunsaturated fatty acids during aging. Curr Neuropharmacol 15: 534-542. doi: 10.2174/1570159X14666160614091311
    [11] Sharon G, Sampson TR, Geschwind DH, et al. (2016) The central nervous system and the gut microbiome. Cell 167: 915-32. doi: 10.1016/j.cell.2016.10.027
    [12] Buffington SA, Di Prisco GV, Auchtung TA, et al. (2016) Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell 165: 1762-1775. doi: 10.1016/j.cell.2016.06.001
    [13] Jašarević E, Rodgers AB, Bale TL (2015) A novel role for maternal stress and microbial transmission in early life programming and neurodevelopment. Neurobiol Stress 1: 81-88. doi: 10.1016/j.ynstr.2014.10.005
    [14] Rosato V, Temple NJ, La Vecchia C, et al. (2019) Mediterranean diet and cardiovascular disease: a systematic review and meta-analysis of observational studies. Eur J Nutr 58: 173-191. doi: 10.1007/s00394-017-1582-0
    [15] Mentella MC, Scaldaferri F, Ricci C, et al. (2019) Cancer and Mediterranean diet: a review. Nutrients 11: 2059. doi: 10.3390/nu11092059
    [16] Martín-Peláez S, Fito M, Castaner O (2020) Mediterranean Diet Effects on Type 2 Diabetes Prevention, Disease Progression, and Related Mechanisms. A Review. Nutrients 12: 2236. doi: 10.3390/nu12082236
    [17] Radd-Vagenas S, Duffy SL, Naismith SL, et al. (2018) Effect of the Mediterranean diet on cognition and brain morphology and function: a systematic review of randomized controlled trials. Am J Clin Nutr 107: 389-404. doi: 10.1093/ajcn/nqx070
    [18] Gardener H, Caunca MR (2018) Mediterranean diet in preventing neurodegenerative diseases. Curr Nutr Rep 7: 10-20. doi: 10.1007/s13668-018-0222-5
    [19] Cremonini AL, Caffa I, Cea M, et al. (2019) Nutrients in the Prevention of Alzheimer's Disease. Oxid Med Cell Longev 2019: 9874159. doi: 10.1155/2019/9874159
    [20] Aridi YS, Walker JL, Wright ORL (2017) The association between the Mediterranean dietary pattern and cognitive health: a systematic review. Nutrients 9: 674. doi: 10.3390/nu9070674
    [21] Mori TA, Beilin LJ (2004) Omega-3 fatty acids and inflammation. Curr Atheroscler Rep 6: 461-467. doi: 10.1007/s11883-004-0087-5
    [22] Esposito K, Nappo F, Giugliano F, et al. (2003) Meal modulation of circulating interleukin 18 and adiponectin concentrations in healthy subjects and in patients with type 2 diabetes mellitus. Am J Clin Nutr 78: 1135-1140. doi: 10.1093/ajcn/78.6.1135
    [23] Román GC, Jackson RE, Gadhia R, et al. (2019) Mediterranean diet: The role of long-chain ω-3 fatty acids in fish; polyphenols in fruits, vegetables, cereals, coffee, tea, cacao and wine; probiotics and vitamins in prevention of stroke, age-related cognitive decline, and Alzheimer disease. Rev Neurol (Paris) 175: 724-741. doi: 10.1016/j.neurol.2019.08.005
    [24] Cutuli D, De Bartolo P, Caporali P, et al. (2014) n-3 polyunsaturated fatty acids supplementation enhances hippocampal functionality in aged mice. Front Aging Neurosci 6: 220. doi: 10.3389/fnagi.2014.00220
    [25] Cutuli D, Pagani M, Caporali P, et al. (2016) Effects of omega-3 fatty acid supplementation on cognitive functions and neural substrates: a voxel-based morphometry study in aged mice. Front Aging Neurosci 8: 38. doi: 10.3389/fnagi.2016.00038
    [26] Innis SM (2008) Dietary omega 3 fatty acids and the developing brain. Brain Res 1237: 35-43. doi: 10.1016/j.brainres.2008.08.078
    [27] Czyż K, Bodkowski R, Herbinger G, et al. (2016) Omega-3 fatty acids and their role in central nervous system-a review. Curr Med Chem 23: 816-831. doi: 10.2174/0929867323666160122114439
    [28] Farkas T, Kitajka K, Fodor E, et al. (2000) Docosahexaenoic acid-containing phospholipid molecular species in brains of vertebrates. Proc Natl Acad Sci 97: 6362-6366. doi: 10.1073/pnas.120157297
    [29] Kitajka K, Puskás LG, Zvara Á, et al. (2002) The role of n-3 polyunsaturated fatty acids in brain: modulation of rat brain gene expression by dietary n-3 fatty acids. Proc Natl Acad Sci USA 99: 2619-2624. doi: 10.1073/pnas.042698699
    [30] Barcelo-Coblijn G, Hőgyes E, Kitajka K, et al. (2003) Modification by docosahexaenoic acid of age-induced alterations in gene expression and molecular composition of rat brain phospholipids. Proc Natl Acad Sci 100: 11321-11326. doi: 10.1073/pnas.1734008100
    [31] Crawford MA, Sinclair AJ (1972) The limitations of whole tissue analysis to define linolenic acid deficiency. J Nutr 102: 1315-1321. doi: 10.1093/jn/102.10.1315
    [32] Crawford MA, Bloom M, Broadhurst CL, et al. (1999) Evidence for the unique function of docosahexaenoic acid during the evolution of the modern hominid brain. Lipids 34: S39-S47. doi: 10.1007/BF02562227
    [33] Bourre JM, Francois M, Youyou A, et al. (1989) The effects of dietary α-linolenic acid on the composition of nerve membranes, enzymatic activity, amplitude of electrophysiological parameters, resistance to poisons and performance of learning tasks in rats. J Nutr 119: 1880-1892. doi: 10.1093/jn/119.12.1880
    [34] Moriguchi T, Greiner RS, Salem N (2000) Behavioral deficits associated with dietary induction of decreased brain docosahexaenoic acid concentration. J Neurochem 75: 2563-2573. doi: 10.1046/j.1471-4159.2000.0752563.x
    [35] Adams PB, Lawson S, Sanigorski A, et al. (1996) Arachidonic acid to eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms of depression. Lipids 31: S157-S161. doi: 10.1007/BF02637069
    [36] Peet M, Laugharne JDE, Mellor J, et al. (1996) Essential fatty acid deficiency in erythrocyte membranes from chronic schizophrenic patients, and the clinical effects of dietary supplementation. Prostaglandins, Leukot Essent Fat Acids 55: 71-75. doi: 10.1016/S0952-3278(96)90148-9
    [37] Freeman MP, Hibbeln JR, Wisner KL, et al. (2006) Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry. J Clin Psychiatry 67: 1954-1967. doi: 10.4088/JCP.v67n1217
    [38] Gupta SC, Tyagi AK, Deshmukh-Taskar P, et al. (2014) Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenols. Arch Biochem Biophys 559: 91-99. doi: 10.1016/
    [39] Anekonda TS (2006) Resveratrol—a boon for treating Alzheimer's disease? Brain Res Rev 52: 316-326. doi: 10.1016/j.brainresrev.2006.04.004
    [40] Frautschy SA, Hu W, Kim P, et al. (2001) Phenolic anti-inflammatory antioxidant reversal of Aβ-induced cognitive deficits and neuropathology. Neurobiol Aging 22: 993-1005. doi: 10.1016/S0197-4580(01)00300-1
    [41] Van Praag H, Lucero MJ, Yeo GW, et al. (2007) Plant-derived flavanol (−) epicatechin enhances angiogenesis and retention of spatial memory in mice. J Neurosci 27: 5869-5878. doi: 10.1523/JNEUROSCI.0914-07.2007
    [42] Rendeiro C, Vauzour D, Rattray M, et al. (2013) Dietary levels of pure flavonoids improve spatial memory performance and increase hippocampal brain-derived neurotrophic factor. PLoS One 8: e63535. doi: 10.1371/journal.pone.0063535
    [43] Letenneur L, Proust-Lima C, Le Gouge A, et al. (2007) Flavonoid intake and cognitive decline over a 10-year period. Am J Epidemiol 165: 1364-1371. doi: 10.1093/aje/kwm036
    [44] Sasaki H, Matsuzaki Y, Meguro K, et al. (1992) Vitamin B12 improves cognitive disturbance in rodents fed a choline-deficient diet. Pharmacol Biochem Behav 43: 635-639. doi: 10.1016/0091-3057(92)90204-S
    [45] Bryan J, Calvaresi E, Hughes D (2002) Short-term folate, vitamin B-12 or vitamin B-6 supplementation slightly affects memory performance but not mood in women of various ages. J Nutr 132: 1345-1356. doi: 10.1093/jn/132.6.1345
    [46] Vogiatzoglou A, Refsum H, Johnston C, et al. (2008) Vitamin B12 status and rate of brain volume loss in community-dwelling elderly. Neurology 71: 826-832. doi: 10.1212/01.wnl.0000325581.26991.f2
    [47] Tangney CC, Aggarwal NT, Li H, et al. (2011) Vitamin B12, cognition, and brain MRI measures: a cross-sectional examination. Neurology 77: 1276-1282. doi: 10.1212/WNL.0b013e3182315a33
    [48] Polverino A, Grimaldi M, Sorrentino P, et al. (2018) Effects of acetylcholine on β-amyloid-induced cPLA2 activation in the TB neuroectodermal cell line: Implications for the pathogenesis of Alzheimer's disease. Cell Mol Neurobiol 38: 817-826. doi: 10.1007/s10571-017-0555-4
    [49] Singh IN, Sorrentino G, Sitar DS, et al. (1997) Indomethacin and nordihydroguaiaretic acid inhibition of amyloid β protein (25–35) activation of phospholipases A2 and D of LA-N-2 cells. Neurosci Lett 222: 5-8. doi: 10.1016/S0304-3940(97)13327-4
    [50] Singh IN, Sorrentino G, Kanfer JN (1998) Activation of LA-N-2 cell phospholipase D by amyloid beta protein (25–35). Neurochem Res 23: 1225-1232. doi: 10.1023/A:1020731813973
    [51] Obeid R, Herrmann W (2006) Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett 580: 2994-3005. doi: 10.1016/j.febslet.2006.04.088
    [52] Perkins AJ, Hendrie HC, Callahan CM, et al. (1999) Association of antioxidants with memory in a multiethnic elderly sample using the Third National Health and Nutrition Examination Survey. Am J Epidemiol 150: 37-44. doi: 10.1093/oxfordjournals.aje.a009915
    [53] Przybelski RJ, Binkley NC (2007) Is vitamin D important for preserving cognition? A positive correlation of serum 25-hydroxyvitamin D concentration with cognitive function. Arch Biochem Biophys 460: 202-205. doi: 10.1016/
    [54] Slinin Y, Paudel M, Taylor BC, et al. (2012) Association between serum 25 (OH) vitamin D and the risk of cognitive decline in older women. J Gerontol A Biol Sci Med Sci 67: 1092-1098. doi: 10.1093/gerona/gls075
    [55] Littlejohns TJ, Henley WE, Lang IA, et al. (2014) Vitamin D and the risk of dementia and Alzheimer disease. Neurology 83: 920-928. doi: 10.1212/WNL.0000000000000755
    [56] Dalton A, Mermier C, Zuhl M (2019) Exercise influence on the microbiome-gut-brain axis. Gut Microbes 10: 555-568. doi: 10.1080/19490976.2018.1562268
    [57] Alam R, Abdolmaleky HM, Zhou J (2017) Microbiome, inflammation, epigenetic alterations, and mental diseases. Am J Med Genet Part B Neuropsychiatr Genet 174: 651-660. doi: 10.1002/ajmg.b.32567
    [58] Rhee SH, Pothoulakis C, Mayer EA (2009) Principles and clinical implications of the brain–gut–enteric microbiota axis. Nat Rev Gastroenterol Hepatol 6: 306-314. doi: 10.1038/nrgastro.2009.35
    [59] Mulak A, Bonaz B (2015) Brain-gut-microbiota axis in Parkinson's disease. World J Gastroenterol WJG 21: 10609-10620. doi: 10.3748/wjg.v21.i37.10609
    [60] Polverino A, Rucco R, Stillitano I, et al. (2020) In amyotrophic lateral sclerosis blood cytokines are altered, but do not correlate with changes in brain topology. Brain Connect 10: 411-421. doi: 10.1089/brain.2020.0741
    [61] Tillisch K (2014) The effects of gut microbiota on CNS function in humans. Gut Microbes 5: 404-410. doi: 10.4161/gmic.29232
    [62] Gabbianelli R, Damiani E (2018) Epigenetics and neurodegeneration: role of early-life nutrition. J Nutr Biochem 57: 1-13. doi: 10.1016/j.jnutbio.2018.01.014
    [63] Lista I, Sorrentino G (2010) Biological mechanisms of physical activity in preventing cognitive decline. Cell Mol Neurobiol 30: 493-503. doi: 10.1007/s10571-009-9488-x
    [64] Businaro R, Ippoliti F, Ricci S, et al. (2012) Alzheimer's disease promotion by obesity: induced mechanisms—molecular links and perspectives. Curr Gerontol Geriatr Res 2012: 986823. doi: 10.1155/2012/986823
    [65] Grundy SM (2016) Metabolic syndrome update. Trends Cardiovasc Med 26: 364-373. doi: 10.1016/j.tcm.2015.10.004
    [66] Tosti V, Bertozzi B, Fontana L (2018) Health benefits of the Mediterranean diet: metabolic and molecular mechanisms. J Gerontol A Biol Sci Med Sci 73: 318-326. doi: 10.1093/gerona/glx227
    [67] Delgado-Morales R, Agís-Balboa RC, Esteller M, et al. (2017) Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders. Clin Epigenetics 9: 67. doi: 10.1186/s13148-017-0365-z
    [68] Deibel SH, Zelinski EL, Keeley RJ, et al. (2015) Epigenetic alterations in the suprachiasmatic nucleus and hippocampus contribute to age-related cognitive decline. Oncotarget 6: 23181-23203. doi: 10.18632/oncotarget.4036
    [69] Gosling AL, Buckley HR, Matisoo-Smith E, et al. (2015) Pacific populations, metabolic disease and ‘Just-So Stories’: A critique of the ‘Thrifty Genotype’ hypothesis in Oceania. Ann Hum Genet 79: 470-480. doi: 10.1111/ahg.12132
    [70] Thompson ME, Wrangham RW (2008) Diet and reproductive function in wild female chimpanzees (Pan troglodytes schweinfurthii) at Kibale National Park, Uganda. Am J Phys Anthropol 135: 171-181. doi: 10.1002/ajpa.20718
    [71] Gibbons A (2007) Paleoanthropology. Food for thought. Science 316: 1558-1560. doi: 10.1126/science.316.5831.1558
    [72] Wells JCK (2007) The thrifty phenotype as an adaptive maternal effect. Biol Rev Camb Philos Soc 82: 143-172. doi: 10.1111/j.1469-185X.2006.00007.x
    [73] Block T, El-Osta A (2017) Epigenetic programming, early life nutrition and the risk of metabolic disease. Atherosclerosis 266: 31-40. doi: 10.1016/j.atherosclerosis.2017.09.003
    [74] Hales CN, Barker DJP (1992) Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 35: 595-601. doi: 10.1007/BF00400248
    [75] Hales CN, Barker DJP (2001) The thrifty phenotype hypothesis: Type 2 diabetes. Br Med Bull 60: 5-20. doi: 10.1093/bmb/60.1.5
    [76] Singhal A, Lucas A (2004) Early origins of cardiovascular disease: is there a unifying hypothesis? Lancet 363: 1642-1645. doi: 10.1016/S0140-6736(04)16210-7
    [77] Kelsey G, Constancia M, Dean WL, et al. (1999) Genomic imprinting of fetal growth. Fetal Program Influ Dev Dis Later Life 73: 84.
    [78] Moore SE, Halsall I, Howarth D, et al. (2001) Glucose, insulin and lipid metabolism in rural Gambians exposed to early malnutrition. Diabet Med 18: 646-653. doi: 10.1046/j.1464-5491.2001.00565.x
    [79] Prentice AM, Rayco-Solon P, Moore SE (2005) Insights from the developing world: thrifty genotypes and thrifty phenotypes. Proc Nutr Soc 64: 153-161. doi: 10.1079/PNS2005421
    [80] Levitan RD, Wendland B (2013) Novel “thrifty” models of increased eating behaviour. Curr Psychiatry Rep 15: 408. doi: 10.1007/s11920-013-0408-x
    [81] Whitmer RA, Gunderson EP, Barrett-Connor E, et al. (2005) Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study. BMJ 330: 1360. doi: 10.1136/bmj.38446.466238.E0
    [82] Xu WL, Atti AR, Gatz M, et al. (2011) Midlife overweight and obesity increase late-life dementia risk: a population-based twin study. Neurology 76: 1568-1574. doi: 10.1212/WNL.0b013e3182190d09
    [83] Dye L, Boyle NB, Champ C, et al. (2017) The relationship between obesity and cognitive health and decline. Proc Nutr Soc 76: 443-454. doi: 10.1017/S0029665117002014
    [84] Shefer G, Marcus Y, Stern N (2013) Is obesity a brain disease? Neurosci Biobehav Rev 37: 2489-2503. doi: 10.1016/j.neubiorev.2013.07.015
    [85] Verstynen TD, Weinstein AM, Schneider WW, et al. (2012) Increased body mass index is associated with a global and distributed decrease in white matter microstructural integrity. Psychosom Med 74: 682-690. doi: 10.1097/PSY.0b013e318261909c
    [86] Willeumier KC, Taylor DV, Amen DG (2011) Elevated BMI is associated with decreased blood flow in the prefrontal cortex using SPECT imaging in healthy adults. Obesity 19: 1095-1097. doi: 10.1038/oby.2011.16
    [87] Cheke LG, Bonnici HM, Clayton NS, et al. (2017) Obesity and insulin resistance are associated with reduced activity in core memory regions of the brain. Neuropsychologia 96: 137-149. doi: 10.1016/j.neuropsychologia.2017.01.013
    [88] Gonzales MM, Tarumi T, Miles SC, et al. (2010) Insulin sensitivity as a mediator of the relationship between BMI and working memory-related brain activation. Obesity 18: 2131-2137. doi: 10.1038/oby.2010.183
    [89] Soubry A (2018) POHaD: why we should study future fathers. Environ Epigenet 4: dvy007. doi: 10.1093/eep/dvy007
    [90] Soubry A, Hoyo C, Jirtle RL, et al. (2014) A paternal environmental legacy: evidence for epigenetic inheritance through the male germ line. Bioessays 36: 359-371. doi: 10.1002/bies.201300113
    [91] Soubry A, Hoyo C, Butt CM, et al. (2017) Human exposure to flame-retardants is associated with aberrant DNA methylation at imprinted genes in sperm. Environ Epigenet 3: dvx003. doi: 10.1093/eep/dvx003
    [92] Shnorhavorian M, Schwartz SM, Stansfeld B, et al. (2017) Differential DNA methylation regions in adult human sperm following adolescent chemotherapy: potential for epigenetic inheritance. PLoS One 12: e0170085. doi: 10.1371/journal.pone.0170085
    [93] Soubry A, Guo L, Huang Z, et al. (2016) Obesity-related DNA methylation at imprinted genes in human sperm: results from the TIEGER study. Clin Epigenet 8: 1-11. doi: 10.1186/s13148-016-0217-2
    [94] Donkin I, Versteyhe S, Ingerslev LR, et al. (2016) Obesity and bariatric surgery drive epigenetic variation of spermatozoa in humans. Cell Metab 23: 369-378. doi: 10.1016/j.cmet.2015.11.004
    [95] Marczylo EL, Amoako AA, Konje JC, et al. (2012) Smoking induces differential miRNA expression in human spermatozoa: a potential transgenerational epigenetic concern? Epigenetics 7: 432-439. doi: 10.4161/epi.19794
    [96] Ouko LA, Shantikumar K, Knezovich J, et al. (2009) Effect of alcohol consumption on CpG methylation in the differentially methylated regions of H19 and IG-DMR in male gametes—Implications for fetal alcohol spectrum disorders. Alcohol Clin Exp Res 33: 1615-1627. doi: 10.1111/j.1530-0277.2009.00993.x
    [97] Fernandez AZ, Siebel AL, El-Osta A (2010) Atherogenic factors and their epigenetic relationships. Int J Vasc Med 2010: 437809.
    [98] Wang J, Wu Z, Li D, et al. (2012) Nutrition, epigenetics, and metabolic syndrome. Antioxid Redox Signal 17: 282-301. doi: 10.1089/ars.2011.4381
    [99] Bakulski KM, Fallin MD (2014) Epigenetic epidemiology: promises for public health research. Environ Mol Mutagen 55: 171-183. doi: 10.1002/em.21850
    [100] Heijmans BT, Tobi EW, Stein AD, et al. (2008) Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA 105: 17046-17049. doi: 10.1073/pnas.0806560105
    [101] Dominguez-Salas P, Cox SE, Prentice AM, et al. (2012) Maternal nutritional status, C1 metabolism and offspring DNA methylation: a review of current evidence in human subjects. Proc Nutr Soc 71: 154-65. doi: 10.1017/S0029665111003338
    [102] Vucetic Z, Kimmel J, Totoki K, et al. (2010) Maternal high-fat diet alters methylation and gene expression of dopamine and opioid-related genes. Endocrinology 151: 4756-4764. doi: 10.1210/en.2010-0505
    [103] Dunford AR, Sangster JM (2017) Maternal and paternal periconceptional nutrition as an indicator of offspring metabolic syndrome risk in later life through epigenetic imprinting: a systematic review. Diabetes Metab Syndr 11: S655-S662. doi: 10.1016/j.dsx.2017.04.021
    [104] Gheorghe CP, Goyal R, Mittal A, et al. (2010) Gene expression in the placenta: maternal stress and epigenetic responses. Int J Dev Biol 54: 507-523. doi: 10.1387/ijdb.082770cg
    [105] Nugent BM, Bale TL (2015) The omniscient placenta: metabolic and epigenetic regulation of fetal programming. Front Neuroendocrinol 39: 28-37. doi: 10.1016/j.yfrne.2015.09.001
    [106] Bale TL, Baram TZ, Brown AS, et al. (2010) Early life programming and neurodevelopmental disorders. Biol Psychiatry 68: 314-319. doi: 10.1016/j.biopsych.2010.05.028
    [107] Reik W, Dean W, Walter J (2001) Epigenetic reprogramming in mammalian development. Science 293: 1089-1093. doi: 10.1126/science.1063443
    [108] Doherty AS, Mann MRW, Tremblay KD, et al. (2000) Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo. Biol Reprod 62: 1526-1535. doi: 10.1095/biolreprod62.6.1526
    [109] Morgan HD, Jin XL, Li A, et al. (2008) The culture of zygotes to the blastocyst stage changes the postnatal expression of an epigentically labile allele, agouti viable yellow, in mice. Biol Reprod 79: 618-623. doi: 10.1095/biolreprod.108.068213
    [110] Lumey LH, Stein AD, Kahn HS, et al. (2007) Cohort profile: the Dutch Hunger Winter families study. Int J Epidemiol 36: 1196-1204. doi: 10.1093/ije/dym126
    [111] Agosti M, Tandoi F, Morlacchi L, et al. (2017) Nutritional and metabolic programming during the first thousand days of life. Pediatr Med Chir 39: 157. doi: 10.4081/pmc.2017.157
    [112] Hanson MA, Gluckman PD (2014) Early developmental conditioning of later health and disease: physiology or pathophysiology? Physiol Rev 94: 1027-1076. doi: 10.1152/physrev.00029.2013
    [113] Burton T, Metcalfe NB (2014) Can environmental conditions experienced in early life influence future generations? Proc R Soc B Biol Sci 281: 20140311. doi: 10.1098/rspb.2014.0311
    [114] Gomez-Verjan JC, Barrera-Vázquez OS, García-Velázquez L, et al. (2020) Epigenetic variations due to nutritional status in early-life and its later impact on aging and disease. Clin Genet 98: 313-321. doi: 10.1111/cge.13748
    [115] Hardy TM, Tollefsbol TO (2011) Epigenetic diet: impact on the epigenome and cancer. Epigenomics 3: 503-518. doi: 10.2217/epi.11.71
    [116] Waterland RA (2006) Assessing the effects of high methionine intake on DNA methylation. J Nutr 136: 1706S-1710S. doi: 10.1093/jn/136.6.1706S
    [117] Mahmoud AM, Ali MM (2019) Methyl donor micronutrients that modify DNA methylation and cancer outcome. Nutrients 11: 608. doi: 10.3390/nu11030608
    [118] Quarchioni E, Possenti V, Ferrante G, et al. (2016) Tobacco smoking and alcohol intake in pregnant and breastfeeding women: preliminary data of the survey PASSI 2014. Epidemiol Prev 40: 76.
    [119] Ceccanti M, Romeo M, Fiorentino D (2004) Alcohol and women: clinical aspects. Ann Ist Super Sanità 40: 5-10.
    [120] Bhatara V, Loudenberg R, Ellis R (2006) Association of attention deficit hyperactivity disorder and gestational alcohol exposure: an exploratory study. J Atten Disord 9: 515-522. doi: 10.1177/1087054705283880
    [121] Hellemans KGC, Verma P, Yoon E, et al. (2008) Prenatal alcohol exposure increases vulnerability to stress and anxiety-like disorders in adulthood. Ann N Y Acad Sci 1144: 154-175. doi: 10.1196/annals.1418.016
    [122] Michaelis EK, Michaelis ML (1994) Cellular and molecular bases of alcohol's teratogenic effects. Alcohol Health Res World 18: 17-21.
    [123] Cartwright MM, Smith SM (1995) Increased cell death and reduced neural crest cell numbers in ethanol-exposed embryos: partial basis for the fetal alcohol syndrome phenotype. Alcohol Clin Exp Res 19: 378-386. doi: 10.1111/j.1530-0277.1995.tb01519.x
    [124] Chen S, Sulik KK (1996) Free radicals and ethanol-induced cytotoxicity in neural crest cells. Alcohol Clin Exp Res 20: 1071-1076. doi: 10.1111/j.1530-0277.1996.tb01948.x
    [125] Resendiz M, Chen Y, Öztürk NC, et al. (2013) Epigenetic medicine and fetal alcohol spectrum disorders. Epigenomics 5: 73-86. doi: 10.2217/epi.12.80
    [126] Perkins A, Lehmann C, Lawrence RC, et al. (2013) Alcohol exposure during development: Impact on the epigenome. Int J Dev Neurosci 31: 391-397. doi: 10.1016/j.ijdevneu.2013.03.010
    [127] Chen YY, Ozturk NC, Zhou FC (2013) DNA methylation program in developing hippocampus and its alteration by alcohol. PLoS One 8: e60503. doi: 10.1371/journal.pone.0060503
    [128] Liu Y, Balaraman Y, Wang G, et al. (2009) Alcohol exposure alters DNA methylation profiles in mouse embryos at early neurulation. Epigenetics 4: 500-511. doi: 10.4161/epi.4.7.9925
    [129] Boschen KE, Keller SM, Roth TL, et al. (2018) Epigenetic mechanisms in alcohol-and adversity-induced developmental origins of neurobehavioral functioning. Neurotoxicol Teratol 66: 63-79. doi: 10.1016/
    [130] Liang F, Diao L, Liu J, et al. (2014) Paternal ethanol exposure and behavioral abnormities in offspring: associated alterations in imprinted gene methylation. Neuropharmacology 81: 126-133. doi: 10.1016/j.neuropharm.2014.01.025
    [131] Conner KE, Bottom RT, Huffman KJ (2020) The impact of paternal alcohol consumption on offspring brain and behavioral development. Alcohol Clin Exp Res 44: 125-140. doi: 10.1111/acer.14245
    [132] Moody L, Chen H, Pan YX (2017) Early-life nutritional programming of cognition—the fundamental role of epigenetic mechanisms in mediating the relation between early-life environment and learning and memory process. Adv Nutr 8: 337-350. doi: 10.3945/an.116.014209
    [133] Fatemi M, Hermann A, Pradhan S, et al. (2001) The activity of the murine DNA methyltransferase Dnmt1 is controlled by interaction of the catalytic domain with the N-terminal part of the enzyme leading to an allosteric activation of the enzyme after binding to methylated DNA. J Mol Biol 309: 1189-1199. doi: 10.1006/jmbi.2001.4709
    [134] Shi Y, Whetstine JR (2007) Dynamic regulation of histone lysine methylation by demethylases. Mol Cell 25: 1-14. doi: 10.1016/j.molcel.2006.12.010
    [135] Tran PV, Kennedy BC, Lien YC, et al. (2015) Fetal iron deficiency induces chromatin remodeling at the Bdnf locus in adult rat hippocampus. Am J Physiol Integr Comp Physiol 308: R276-R282. doi: 10.1152/ajpregu.00429.2014
    [136] Hou N, Ren L, Gong M, et al. (2015) Vitamin A deficiency impairs spatial learning and memory: the mechanism of abnormal CBP-dependent histone acetylation regulated by retinoic acid receptor alpha. Mol Neurobiol 51: 633-47. doi: 10.1007/s12035-014-8741-6
    [137] Athanasopoulos D, Karagiannis G, Tsolaki M (2016) Recent findings in Alzheimer disease and nutrition focusing on epigenetics. Adv Nutr 7: 917-927. doi: 10.3945/an.116.012229
    [138] Eidelman AI, Schanler RJ (2012) Breastfeeding and the use of human milk. Pediatrics 129: e827-e841. doi: 10.1542/peds.2011-3552
    [139] Sjögren YM, Tomicic S, Lundberg A, et al. (2009) Influence of early gut microbiota on the maturation of childhood mucosal and systemic immune responses: gut microbiota and immune responses. Clin Exp Allergy 39: 1842-1851. doi: 10.1111/j.1365-2222.2009.03326.x
    [140] Verduci E, Banderali G, Barberi S, et al. (2014) Epigenetic effects of human breast milk. Nutrients 6: 1711-1724. doi: 10.3390/nu6041711
    [141] Campoy C, Escolano-Margarit MV, Anjos T, et al. (2012) Omega 3 fatty acids on child growth, visual acuity and neurodevelopment. Br J Nutr 107: S85-S106. doi: 10.1017/S0007114512001493
    [142] Schuchardt JP, Huss M, Stauss-Grabo M, et al. (2010) Significance of long-chain polyunsaturated fatty acids (PUFAs) for the development and behaviour of children. Eur J Pediatr 169: 149-164. doi: 10.1007/s00431-009-1035-8
    [143] Innis SM (2007) Dietary (n-3) fatty acids and brain development. J Nutr 137: 855-859. doi: 10.1093/jn/137.4.855
    [144] Martinez M (1992) Tissue levels of polyunsaturated fatty acids during early human development. J Pediatr 120: S129-S138. doi: 10.1016/S0022-3476(05)81247-8
    [145] Innis SM (2009) Omega-3 Fatty acids and neural development to 2 years of age: do we know enough for dietary recommendations? J Pediatr Gastroenterol Nutr 48: S16-S24. doi: 10.1097/MPG.0b013e31819773cf
    [146] Makrides M, Simmer K, Goggin M, et al. (1993) Erythrocyte docosahexaenoic acid correlates with the visual response of healthy, term infants. Pediatr Res 33: 425-427.
    [147] Binns C, Lee M, Low WY (2016) The long-term public health benefits of breastfeeding. Asia Pacific J Public Health 28: 7-14. doi: 10.1177/1010539515624964
    [148] Stettler N, Stallings VA, Troxel AB, et al. (2005) Weight gain in the first week of life and overweight in adulthood: a cohort study of European American subjects fed infant formula. Circulation 111: 1897-1903. doi: 10.1161/01.CIR.0000161797.67671.A7
    [149] Mayer EA, Knight R, Mazmanian SK, et al. (2014) Gut microbes and the brain: paradigm shift in neuroscience. J Neurosci 34: 15490-15496. doi: 10.1523/JNEUROSCI.3299-14.2014
    [150] Kasubuchi M, Hasegawa S, Hiramatsu T, et al. (2015) Dietary gut microbial metabolites, short-chain fatty acids, and host metabolic regulation. Nutrients 7: 2839-2849. doi: 10.3390/nu7042839
    [151] Dalile B, Van Oudenhove L, Vervliet B, et al. (2019) The role of short-chain fatty acids in microbiota–gut–brain communication. Nat Rev Gastroenterol Hepatol 16: 461-478. doi: 10.1038/s41575-019-0157-3
    [152] Kelly CJ, Zheng L, Campbell EL, et al. (2015) Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. Cell Host Microbe 17: 662-671. doi: 10.1016/j.chom.2015.03.005
    [153] Tong L, Wang Y, Wang Z, et al. (2016) Propionate ameliorates dextran sodium sulfate-induced colitis by improving intestinal barrier function and reducing inflammation and oxidative stress. Front Pharmacol 7: 253. doi: 10.3389/fphar.2016.00253
    [154] Simeoli R, Mattace Raso G, Pirozzi C, et al. (2017) An orally administered butyrate-releasing derivative reduces neutrophil recruitment and inflammation in dextran sulphate sodium-induced murine colitis. Br J Pharmacol 174: 1484-1496. doi: 10.1111/bph.13637
    [155] Byrn MA, Sheean PM (2019) Serum 25 (OH) D and cognition: a narrative review of current evidence. Nutrients 11: 729. doi: 10.3390/nu11040729
    [156] Landel V, Annweiler C, Millet P, et al. (2016) Vitamin D, cognition and Alzheimer's disease: the therapeutic benefit is in the D-tails. J Alzheimers Dis 53: 419-444. doi: 10.3233/JAD-150943
    [157] Annweiler C, Montero-Odasso M, Llewellyn DJ, et al. (2013) Meta-analysis of memory and executive dysfunctions in relation to vitamin D. J Alzheimers Dis 37: 147-171. doi: 10.3233/JAD-130452
    [158] Brouwer-Brolsma EM, Dhonukshe-Rutten RAM, van Wijngaarden JP, et al. (2015) Cognitive performance: a cross-sectional study on serum vitamin D and its interplay with glucose homeostasis in dutch older adults. J Am Med Dir Assoc 16: 621-627. doi: 10.1016/j.jamda.2015.02.013
    [159] Pettersen JA, Fontes S, Duke CL (2014) The effects of Vitamin D Insufficiency and Seasonal Decrease on cognition. Can J Neurol Sci 41: 459-465. doi: 10.1017/S0317167100018497
    [160] Stillwell W, Shaikh SR, Zerouga M, et al. (2005) Docosahexaenoic acid affects cell signaling by altering lipid rafts. Reprod Nutr Dev 45: 559-579. doi: 10.1051/rnd:2005046
    [161] Chalon S (2006) Omega-3 fatty acids and monoamine neurotransmission. Prostaglandins Leukot Essent Fat Acids 75: 259-269. doi: 10.1016/j.plefa.2006.07.005
    [162] Bazan NG (2006) Cell survival matters: docosahexaenoic acid signaling, neuroprotection and photoreceptors. Trends Neurosci 29: 263-271. doi: 10.1016/j.tins.2006.03.005
    [163] Vreugdenhil M, Bruehl C, Voskuyl RA, et al. (1996) Polyunsaturated fatty acids modulate sodium and calcium currents in CA1 neurons. Proc Natl Acad Sci USA 93: 12559-12563. doi: 10.1073/pnas.93.22.12559
    [164] Bakulski KM, Dolinoy DC, Sartor MA, et al. (2012) Genome-wide DNA methylation differences between late-onset Alzheimer's disease and cognitively normal controls in human frontal cortex. J Alzheimers Dis 29: 571-588. doi: 10.3233/JAD-2012-111223
    [165] Laurin D, Verreault R, Lindsay J, et al. (2001) Physical activity and risk of cognitive impairment and dementia in elderly persons. Arch Neurol 58: 498-504. doi: 10.1001/archneur.58.3.498
    [166] Fratiglioni L, Wang HX (2007) Brain reserve hypothesis in dementia. J Alzheimers Dis 12: 11-22. doi: 10.3233/JAD-2007-12103
    [167] Mandel S, Amit T, Bar-Am O, et al. (2007) Iron dysregulation in Alzheimer's disease: multimodal brain permeable iron chelating drugs, possessing neuroprotective-neurorescue and amyloid precursor protein-processing regulatory activities as therapeutic agents. Prog Neurobiol 82: 348-360. doi: 10.1016/j.pneurobio.2007.06.001
    [168] Rezai-Zadeh K, Shytle D, Sun N, et al. (2005) Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J Neurosci 25: 8807-8814. doi: 10.1523/JNEUROSCI.1521-05.2005
    [169] Gelfo F, Petrosini L, Graziano A, et al. (2013) Cortical metabolic deficits in a rat model of cholinergic basal forebrain degeneration. Neurochem Res 38: 2114-2123. doi: 10.1007/s11064-013-1120-2
    [170] Bakulski KM, Rozek SL, Dolinoy CD, et al. (2012) Alzheimer's disease and environmental exposure to lead: the epidemiologic evidence and potential role of epigenetics. Curr Alzheimer Res 9: 563-573. doi: 10.2174/156720512800617991
    [171] Mastroeni D, Grover A, Delvaux E, et al. (2010) Epigenetic changes in Alzheimer's disease: decrements in DNA methylation. Neurobiol Aging 31: 2025-2037. doi: 10.1016/j.neurobiolaging.2008.12.005
    [172] Fuso A (2013) The ‘golden age’ of DNA methylation in neurodegenerative diseases. Clin Chem Lab Med 51: 523-534. doi: 10.1515/cclm-2012-0618
    [173] Fuso A, Scarpa S (2011) One-carbon metabolism and Alzheimer's disease: is it all a methylation matter? Neurobiol Aging 32: 1192-1195. doi: 10.1016/j.neurobiolaging.2011.01.012
    [174] Fuso A, Nicolia V, Ricceri L, et al. (2012) S-adenosylmethionine reduces the progress of the Alzheimer-like features induced by B-vitamin deficiency in mice. Neurobiol Aging 33: 1482.e1-1482.e16. doi: 10.1016/j.neurobiolaging.2011.12.013
    [175] Klein CJ, Botuyan M-V, Wu Y, et al. (2011) Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Nat Genet 43: 595-600. doi: 10.1038/ng.830
    [176] Winkelmann J, Lin L, Schormair B, et al. (2012) Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy. Hum Mol Genet 21: 2205-2210. doi: 10.1093/hmg/dds035
    [177] Mohajeri MH, Troesch B, Weber P (2015) Inadequate supply of vitamins and DHA in the elderly: implications for brain aging and Alzheimer-type dementia. Nutrition 31: 261-275. doi: 10.1016/j.nut.2014.06.016
    [178] Araújo JR, Martel F, Borges N, et al. (2015) Folates and aging: Role in mild cognitive impairment, dementia and depression. Ageing Res Rev 22: 9-19. doi: 10.1016/j.arr.2015.04.005
    [179] De Jager CA, Oulhaj A, Jacoby R, et al. (2012) Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial. Int J Geriatr Psychiatry 27: 592-600. doi: 10.1002/gps.2758
    [180] Burdge GC, Lillycrop KA (2014) Fatty acids and epigenetics. Curr Opin Clin Nutr Metab Care 17: 156-161. doi: 10.1097/MCO.0000000000000023
    [181] Wang X, Hjorth E, Vedin I, et al. (2015) Effects of n-3 FA supplementation on the release of proresolving lipid mediators by blood mononuclear cells: the OmegAD study. J Lipid Res 56: 674-681. doi: 10.1194/jlr.P055418
    [182] Chiu S, Woodbury-Fariña MA, Shad MU, et al. (2014) The role of nutrient-based epigenetic changes in buffering against stress, aging, and Alzheimer's disease. Psychiatr Clin North Am 37: 591-623. doi: 10.1016/j.psc.2014.09.001
  • Reader Comments
  • © 2021 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (
通讯作者: 陈斌,
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索


Article views(3886) PDF downloads(248) Cited by(7)

Article outline

Figures and Tables

Figures(5)  /  Tables(2)


DownLoad:  Full-Size Img  PowerPoint